Disclosure of Invention
Based on a great deal of clinical research, the invention aims to provide a large-diameter artificial cornea endothelial piece; a further object is to eliminate corneal oedema while functioning as a barrier to aqueous humor by the design of the oxygen permeable holes (full holes, laces, added loops); further aims at reducing complications such as displacement and falling off of a cornea implant after operation by using the suction disc (circular, elliptic and annular) to ensure that the cornea implant has the advantages of high adhesion and high oxygen permeability.
The invention is based on foldable transparent optical material, and makes it into large diameter artificial cornea endothelial sheet with curvature and sucking disc and/or oxygen permeable holes in the periphery.
The artificial cornea endothelial sheet provided by the invention has the total diameter of 7.0-9.0mm, the thickness of 25.0-70.0 mu m and the curvature radius of 6.0-9.0mm, and is provided with oxygen permeation holes; the design of the oxygen permeation hole comprises one of perforation (full hole), lace shape (half hole) and peripheral loop adding, or two or more of perforation (full hole), lace shape (half hole) and peripheral loop adding.
Preferably, the artificial cornea endothelial sheet comprises a central optical zone 1 and a peripheral zone 2, wherein the diameter of the central optical zone 1 is 5.0-7.0mm, the peripheral zone 2 is positioned outside the central optical zone 1, the oxygen permeation holes 3 are positioned in the peripheral zone 2, the number of the oxygen permeation holes is 2-8, and the total area is 0.5-5.3mm 2 。
Preferably, the shape of the oxygen permeable holes 3 includes a circular shape, an elliptical shape, a semicircular shape, a lace shape, and is uniformly or unevenly distributed in the peripheral area 2.
Preferably, the shape of the oxygen permeation hole 3 adopting a punching design is round or oval, and the diameter of the oxygen permeation hole 3 is 0.2-0.6mm.
Preferably, the oxygen permeation holes 3 are designed in a lace shape, the number of the oxygen permeation holes is 4-8, the shape of the oxygen permeation holes is lace-shaped, semicircular or semi-elliptical, the height of the oxygen permeation holes 3 is 0.5-0.75mm, and the arc diameter of the edge is 1.0-1.5mm.
Preferably, the oxygen permeation hole 3 adopts a design of adding a loop, the edge of the artificial cornea endothelial piece is provided with a loop 5, and the loop 5 and the central optical zone 1 or the peripheral zone 2 form the oxygen permeation hole 3.
Preferably, the edge of the artificial cornea endothelial sheet is provided with a loop 5, the loop 5 and the central optical zone 1 or the peripheral zone 2 form an oxygen permeation hole 3, the hole height of the oxygen permeation hole 3 is 0.5-0.75mm, and the side arc diameter is 1.0-1.5mm.
Preferably, the oxygen permeable aperture 3 is a hole or void formed by the outer edges of the central optic zone 1 or peripheral zone 2 between the haptics 5 and their ends in the shape of a crescent, oval, semi-circular or semi-oval, etc.
Preferably, the oxygen permeable holes 3 formed in the peripheral region 2 are co-existing with the oxygen permeable holes 3 formed by the haptics.
More preferably, the artificial cornea endothelial piece is provided with an oxygen permeation hole 3 and a sucker 4, wherein the sucker 4 is positioned on the front side of the artificial cornea endothelial piece, has a depth of 5.0-10.0 mu m and a diameter or width of 0.2-0.5mm.
The sucker 4 is positioned on the front side or the convex surface of the artificial cornea endothelial piece, namely, on the side close to the cornea back stroma when the artificial cornea endothelial piece is implanted into the anterior chamber of human eyes, the sucker 4 can be completely positioned in the peripheral area 2 and can also be partially positioned in the central optical area 1, when the artificial cornea endothelial piece is placed on the eyes, aqueous humor and air in the sucker are discharged in the operation, so that negative pressure is generated in the sucker, and the adhesion of the artificial cornea endothelial piece and the cornea back stroma is improved.
Preferably, the material of the artificial cornea endothelial sheet is an acrylic material selected from hydroxyethyl methacrylate/methyl methacrylate copolymer, polymethyl methacrylate, polyhydroxy methacrylate, acrylic acid hydrogel, methacrylic acid hydrogel and the like.
Advantageous effects
The large-diameter artificial cornea endothelial sheet provided by the invention is a transparent and nondegradable optical material, and the design of the sucker (circular and annular) and the oxygen permeation hole (comprising perforation, lace shape and peripheral loop) ensures that the large-diameter artificial cornea endothelial sheet plays a role in isolating aqueous humor, has the advantages of high adhesion and high oxygen permeation while eliminating corneal edema, can meet nutrients required by normal metabolism of cornea stroma and maintains normal cornea thickness; under the condition of no modification, the design of the sucker and the oxygen permeation hole increases the adhesiveness between the artificial endothelial piece and the cornea back matrix from the physical angle, and the large diameter can increase the stability of the endothelial piece and reduce the risk of the postoperative cornea implant falling off. The artificial endothelial cell is extremely soft and easy to fold, can be implanted into the anterior chamber under the condition of small incision, does not need to load cells, does not need to consider the problem of cell damage in the operation process, greatly reduces the operation difficulty, and further reduces complications such as excessive loss of cornea endothelial cells, shift or drop of cornea implant after operation.
The large-diameter cornea implant provided by the invention is expected to replace the traditional donor cornea endothelial implant, so that the number of cornea transplants is reduced.
Detailed Description
The invention is further illustrated by the following examples which illustrate the invention, which are intended to be illustrative only and should not be construed as limiting the scope of the invention. Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The large-diameter artificial cornea endothelial piece refers to an artificial cornea endothelial piece with the diameter of 7.0-9.0mm, and the large diameter is smaller than 7mm compared with the artificial cornea endothelial piece, cornea implant and the like which are commonly adopted in the prior art, and the diameter of the artificial cornea endothelial piece provided by the invention is relatively larger.
The sucker is a dent which is positioned on the front side or the convex surface of the artificial cornea endothelial sheet, is wholly or partially positioned in the peripheral area and is oriented to the back side or the concave surface of the artificial cornea endothelial sheet.
The cross section of the sucker is round or annular, and the bottom of the concave is hemispherical. The diameter of the suction cup is the diameter of the largest cross section of the circular suction cup. The suction cup width is the width of the largest cross section of the annular suction cup. The depth of the sucker is the concave depth of the circular or annular sucker towards the front side of the artificial cornea endothelial sheet.
The "haptics" refer to semi-circular or semi-elliptical support portions of the peripheral region.
The diameter of the oxygen permeation Kong Bianhu is the diameter of a circle where the oxygen permeation holes such as lace, semicircle, semi-ellipse and the like are located.
Oxygen permeable Kong Konggao: the maximum diameter between the circle of the lace-shaped, semicircular, semi-elliptic and other oxygen permeation holes and the circle of the inner lining piece.
The back side or concave surface of the artificial cornea endothelial piece refers to the surface of the artificial cornea endothelial piece, which is close to aqueous humor when the artificial cornea endothelial piece is implanted into the anterior chamber of human eye.
The anterior or convex surface of the artificial corneal endothelial sheet refers to the surface of the artificial corneal endothelial sheet that is adjacent to the posterior stroma of the cornea when the artificial corneal endothelial sheet is implanted into the anterior chamber of a human eye.
The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The source of the artificial cornea endothelial sheet is not particularly limited in the present invention, and the artificial cornea endothelial sheet known in the art may be used. In the embodiment of the invention, the large-diameter artificial cornea endothelial sheet is self-made by Shandong university of first medical science ophthalmic institute.
Parameters related to the inner sheets of the prosthesis
1. The artificial endothelial sheet material is acrylic acid esters, and can be selected from one or more of hydroxyethyl methacrylate/methyl methacrylate copolymer, polymethyl methacrylate, polyhydroxy ethyl methacrylate, acrylic acid hydrogel and methacrylic acid hydrogel.
2. Transmittance: the light transmittance of the artificial endothelial sheet gradually increases along with the increase of the wavelength of light waves in the wavelength range of 300-800nm, and the light transmittance can reach 79% -85% in the wavelength range of more than 400 nm.
In some embodiments, the artificial cornea endothelial sheet provided by the invention comprises a central optical zone 1 and a peripheral zone 2 as shown in figure 1, wherein no obvious limit exists between the central optical zone 1 and the peripheral zone 2, the total diameter of the cornea endothelial sheet is 7.0-9.0mm, the thickness is 25.0-70.0 mu m, the curvature radius is 6.0-9.0mm, the diameter of the central optical zone 1 is 5.0-7.0mm, the peripheral zone 2 is positioned on the extension of the central optical zone 1, and the artificial cornea endothelial sheet comprises at least 2 oxygen permeation holes 3, the diameter of the oxygen permeation holes 3 is 0.2-0.6mm, and the total area is 0.5-5.3mm 2 。
In some embodiments, the oxygen permeable holes 3 extend through the artificial cornea endothelial sheet, all or part of which are located in the peripheral zone 2, forming a complete circle, semicircle, ellipse or other shape on the anterior and posterior sides of the artificial cornea endothelial sheet (fig. 1A, B, D, E).
In other embodiments, the oxygen permeable holes 3 are located at the edge of the peripheral region 2 of the artificial cornea endothelial sheet, and form incomplete shapes such as semicircular, semi-elliptical, lace-like, etc. on the front and back sides of the artificial cornea endothelial sheet (fig. 1C).
In other embodiments, at least 2 haptics 5 are provided at the edge of the artificial cornea endothelial piece, the haptics 5 are connected with the peripheral area 2, the hollow between the two (the hole formed by the outer edge of the peripheral area between the haptics and two ends thereof) is the oxygen permeation hole 3, the height of the oxygen permeation hole 3 is 0.5-0.75mm, and the arc diameter of the edge is 1.0-1.5mm (fig. 1B).
In other embodiments, the area of the peripheral zone 2 is 0.0mm, at least 2 haptics 5 are arranged at the edge of the artificial cornea endothelial piece, the haptics 5 are connected with the central optical zone 1, the hollow space between the two haptics (the hole formed by the outer edge of the central optical zone between the haptics and the two ends) is the oxygen permeation hole 3, the hole height of the oxygen permeation hole 3 is 0.5-0.75mm, and the side arc diameter is 1.0-1.5mm (fig. 1B).
In some embodiments, the artificial cornea endothelial piece provided by the present invention is further provided with a suction cup 4 (fig. 1, D, E), wherein the opening of the suction cup 4 is located on the convex surface of the artificial cornea endothelial piece, i.e. on one side close to the posterior stroma of the cornea when the artificial cornea endothelial piece is implanted into the anterior chamber of the eye, and is recessed towards the other side of the artificial cornea endothelial piece, but does not penetrate the artificial cornea endothelial piece, and the recess is the suction cup 4. When the artificial cornea endothelial sheet is applied to the anterior chamber of the eye, aqueous humor and air in the sucker are discharged during operation, so that negative pressure is generated in the sucker, and the adhesion between the artificial cornea endothelial sheet and the matrix behind the cornea is improved.
In some embodiments, the suction cups 4 are located entirely within the peripheral zone 2 (fig. 1D); in other embodiments, the suction cup 4 is partially within the peripheral zone 2 and partially within the central optical zone 1 (fig. 1E); the depth of the sucker 4 is 5.0-10.0 mu m, and the width is 0.2-0.5mm.
In other embodiments, the suction cup 4 is formed in a ring shape having a width of 0.2-0.5mm in the peripheral region 2 of the anterior side of the artificial cornea endothelial sheet, and is formed with a recess having a depth of 5.0-10.0 μm toward the posterior side of the artificial cornea endothelial sheet.
Example 1: preparation of large diameter Artificial endothelial sheet (full pore)
The artificial endothelial piece is prepared by adopting the hydroxyethyl methacrylate/methyl methacrylate copolymer, and the artificial endothelial piece provided by the invention is obtained after drilling by a micro-cutter, and the light transmittance of the artificial endothelial piece is 79% -83% in the wavelength range of more than 400 nm.
FIG. 2A is a diagram showing the obtained artificial endothelial sheet having a diameter of 8.0mm, a thickness of 50.0 μm, a radius of curvature of 7.32mm, a central optical zone 1 of 6.5mm, 4 peripheral circular or elliptical oxygen permeation holes 3 (uniformly or unevenly distributed), a diameter of 0.5mm, and a total area of holes of 0.785mm 2 。
Example 2: preparation of large diameter Artificial endothelial sheet (full pore)
The artificial endothelial sheet is prepared by adopting acrylic acid hydrogel, and the artificial endothelial sheet provided by the invention is obtained after drilling by a micro-cutter, and has light transmittance of 80% -85% in a wavelength range of more than 400 nm.
FIG. 3A is a schematic plan view of an artificial endothelial sheet having a diameter of 8.0mm, a thickness of 25.0 μm, a radius of curvature of 9.0mm, a central optical zone of 5.0mm, surrounding 8 circular oxygen permeable holes (uniformly distributed), a diameter of 0.4mm, and a total area of holes of 1.0mm 2 。
Example 3: preparation of large diameter artificial endothelial sheet (full hole, suction cup)
The artificial endothelial sheet is prepared by adopting polymethyl methacrylate, and the light transmittance of the artificial endothelial sheet provided by the invention is 79% -84% in the wavelength range of more than 400nm after drilling by a micro-cutter.
FIG. 3B is a schematic plan view of an artificial endothelial sheet having a diameter of 8.0mm, a thickness of 25.0 μm, a radius of curvature of 9.0mm, a central optical zone of 7.0mm, 8 circular oxygen permeable holes in the peripheral zone, 8 circular suction cups, the oxygen permeable holes overlapping the suction cups and being uniformly distributed, the oxygen permeable holes having a diameter of 0.6mm, the suction cups having a diameter of 0.25mm, and a depth of 10.0 μm.
Example 4: preparation of large diameter artificial endothelial sheet (full hole, suction cup)
The artificial endothelial sheet is prepared by adopting methacrylic acid hydrogel, and the artificial endothelial sheet provided by the invention is obtained after drilling by a micro-cutter, and has light transmittance of 81-83% in a wavelength range of more than 400 nm.
FIG. 3C is a schematic plan view of an artificial endothelial sheet having a diameter of 8.0mm, a thickness of 70.0 μm, a radius of curvature of 9.0mm, a central optical zone of 6.5mm, 8 circular oxygen permeable holes in the peripheral zone, an annular suction cup at the edge of the central optical zone on the front side of the artificial endothelial sheet, an oxygen permeable hole diameter of 0.4mm, and a total hole area of 1.0mm 2 The width of the suction cup was 0.2mm and the depth was 5.0. Mu.m.
Example 5: preparation of large diameter artificial endothelial sheet (lace)
The artificial endothelial piece is prepared by adopting the hydroxyethyl methacrylate/methyl methacrylate copolymer, and the artificial endothelial piece provided by the invention is obtained after trephine drilling, and the light transmittance is 79% -83% in the wavelength range of more than 400 nm.
FIG. 2B is a physical diagram of the preparation of the inventors, showing that the total diameter of the corneal endothelial sheet is 8.0mm, the thickness is 50.0 μm, the radius of curvature is 7.32mm, the central optical zone is 6.5mm, the peripheral 6 oxygen-permeable holes are oxygen-permeable Kong Konggao is 0.75mm, the side arc diameter is 1.5mm, and the total area of the holes is 5.3mm 2 。
Example 6: preparation of large diameter artificial endothelial sheet (lace, suction cup)
The artificial inner skin is prepared by adopting acrylic acid hydrogel, and the artificial inner skin provided by the invention is obtained after trepanning and drilling, and the light transmittance is 80% -85% in the wavelength range of more than 400 nm.
As shown in FIG. 4, which is a schematic plan view of an artificial endothelial sheet, the total diameter of the artificial corneal endothelial sheet is 9.0mm, the thickness is 70.0 μm, the radius of curvature is 6.0mm, the diameter of the central optical zone is 6.5mm, the periphery contains 6 oxygen permeation holes, the oxygen permeation Kong Konggao is 0.5mm, the arc diameter of the edge is 1.0mm, the depth of the suction cup is 5.0 μm, and the diameter of the suction cup is 0.5mm.
Example 7: preparation of Large diameter Artificial endothelial sheet (with haptic)
The artificial endothelial sheet is prepared by adopting the poly (hydroxyethyl methacrylate), and the light transmittance is 79-85% in the wavelength range of more than 400 nm.
As shown in FIG. 5, the total diameter of the artificial cornea endothelial sheet is 8.0mm, the thickness is 50.0 μm, the radius of curvature is 9.0mm, the diameter of the central optical zone is 7.0mm, 4 evenly distributed haptics 5 are arranged outside the peripheral zone, the oxygen permeation Kong Konggao is 0.75mm, the side arc diameter is 1.5mm, and the total area of the hole is 3.5mm 2 。
Example 8: preparation of large diameter Artificial endothelial sheet (suction cup)
The artificial endothelial sheet is prepared by adopting hydroxyethyl methacrylate/methyl methacrylate copolymer, and the light transmittance is 79% -83% in the wavelength range of more than 400 nm.
The artificial cornea endothelial sheet has a diameter of 8.0mm, a thickness of 50.0 μm, a radius of curvature of 9.0mm, a central optical zone of 5.0mm, a peripheral zone with annular suction cups, a width of 0.3mm, and a depth of 5.0 μm.
Example 9: preparation of Large diameter Artificial endothelial sheet (full hole, added loop)
The artificial endothelial sheet is prepared by adopting polymethyl methacrylate, and the light transmittance of the artificial endothelial sheet provided by the invention is 79% -84% in the wavelength range of more than 400nm after drilling by a micro-cutter.
The artificial cornea endothelial piece has a diameter of 8.0mm, a thickness of 25.0 μm, a radius of curvature of 9.0mm, a central optical zone of 5.0mm, and 8 circular oxygen permeable holes in the peripheral zone, the diameter of the oxygen permeable holes being 0.6mm. The peripheral zone is also provided with 4 evenly distributed loop pieces, the oxygen permeation Kong Konggao is 0.75mm, and the side arc diameter is 1.5mm.
Example 10: preparation of large diameter Artificial endothelial sheet (full hole, suction cup, and haptic)
The artificial endothelial sheet is prepared by adopting methacrylic acid hydrogel, and the artificial endothelial sheet provided by the invention is obtained after drilling by a micro-cutter, and has light transmittance of 81-83% in a wavelength range of more than 400 nm.
The artificial cornea endothelial sheet has a diameter of 8.0mm, a thickness of 70.0 μm, a radius of curvature of 9.0mm, a central optical zone of 5.0mm, 8 circular oxygen permeation holes in the peripheral zone, and annular suction cups at the edge of the central optical zone, wherein the diameter of the oxygen permeation holes is 0.4mm, the width of the suction cups is 0.2mm, and the depth is 8.0 μm. The peripheral zone is also provided with 4 evenly distributed loop pieces, the oxygen permeation Kong Konggao is 0.5mm, and the side arc diameter is 1.0mm.
Animal experiment
1. Materials and methods
1.1 laboratory animals
35 New Zealand white rabbits, 3.0-3.5Kg in weight, male rabbits.
1.2 grouping
35 New Zealand white rabbits were randomly divided into seven groups of 5.
(1) Unpunched group: the endothelium in the central region of the rabbit cornea was stripped and a large diameter artificial cornea endothelial sheet without punching was implanted (artificial cornea endothelial sheet prepared in example 1 was not subjected to punching treatment).
(2) Full well group: the endothelium in the central region of the rabbit cornea was stripped and a full-aperture large diameter artificial corneal endothelial sheet prepared in example 1 was implanted.
(3) Lace-shaped group: the endothelial layer of the central area of the rabbit cornea was stripped, and the lace-shaped large-diameter artificial cornea endothelial piece prepared in example 5 was implanted.
(4) Haptic group: the endothelial of the central area of the rabbit cornea was stripped, and a large-diameter artificial corneal endothelial sheet with a loop prepared in example 7 was implanted.
(5) Suction cup group: the endothelium in the central area of the rabbit cornea was stripped, and a large-diameter artificial cornea endothelial sheet prepared in example 8 and provided with annular sucking discs in the peripheral area without punching was implanted.
(6) Full aperture/haptic set: the endothelial of the central area of the rabbit cornea was stripped, and a full-hole, haptic-added large-diameter artificial corneal endothelial sheet prepared in example 9 was implanted.
(7) Full aperture/suction cup/haptic set: the endothelium in the central area of the rabbit cornea was stripped, and a full-aperture, suction cup, and haptic large-diameter artificial cornea endothelial piece prepared in example 10 was implanted.
1.3 construction of corneal endothelial decompensation animal model
(1) 25.0mg/kg sodium pentobarbital ear margin was intravenously injected to anesthetize New Zealand white rabbits.
(2) The 0.5% procaine hydrochloride is dripped on the surface of the rabbit cornea to locally relieve pain.
(3) The conjunctival sac was rinsed with 0.9% sodium chloride injection solution and the ocular surface was thoroughly cleaned using a cotton swab.
(4) A corresponding sized trephine was used to imprint the center of the epithelial surface of the rabbit cornea.
(5) A15-degree puncture knife is used for making a puncture at the limbus at the 12 point position, a 0.02mg/mL card Mi Kelin injection is injected for miosis, and a viscoelastic agent is injected for forming the anterior chamber.
(6) The endothelium marked in the center of the cornea was removed using a 1ml syringe needle and a crystal alignment hook.
(7) The anterior chamber was flushed with 0.9% sodium chloride injection to displace the viscoelastic.
(8) 4.0mg/mL gentamicin injection and heparin sodium injection are sequentially injected into the anterior chamber, so that the inflammatory reaction of the anterior chamber is reduced.
(9) Re-injecting viscoelastic agent to form anterior chamber, and implanting the non-perforated artificial cornea endothelial sheet into the non-perforated group; the punch group is implanted with the full-hole artificial cornea endothelial sheet prepared in the example 1; the lace-shaped artificial cornea endothelial sheets prepared in example 5 are implanted in the lace-shaped group; haptic group implantation the haptic-added artificial corneal endothelial sheet prepared in example 7; suction cup group implantation example 8 large diameter artificial cornea endothelial sheet without perforation and with annular suction cup in peripheral area; full aperture/haptic set implantation the full aperture/haptic large diameter artificial corneal endothelial sheet prepared in example 9. Full aperture/suction cup/haptic group implantation the full aperture, suction cup, haptic large diameter artificial corneal endothelial sheet prepared in example 10.
(10) The artificial corneal endothelial sheet is folded and placed into the anterior chamber using toothless forceps and the corneal implant is secured to the central scraping zone endothelium using a positioning hook.
(11) The anterior chamber was again rinsed with 0.9% sodium chloride injection to replace the viscoelastic.
(12) The incision was sutured using a 10-0 suture and anterior chamber insufflation was performed using an insulin needle.
2. Results
Corneal observations and central thickness measurements were made on postoperative day 1, day 7, day 14 using slit lamp, anterior ocular segment OCT (see table 1, fig. 6). Cornea OCT shows that on the 1 st day after operation, artificial endothelial sheets fall off (100%) in the group rabbits without perforation, the endothelial sheets are usually located in the anterior chamber below after falling off, and the falling-off proportions of the other groups of artificial endothelial sheets are respectively as follows: 20% of full hole group, 40% of lace group, 40% of loop adding group, 20% of sucking disc group, 20% of full hole/loop adding group and 20% of full hole/sucking disc/loop adding group. The lace-shaped group and the tab-added group still have corneal oedema after 1 week of operation, but seven groups recover the transparency of the inner cornea after 2 weeks of operation. At 2 weeks, the non-perforated group cornea thickness averaged (211+ -33 μm), the perforated group cornea thickness averaged (293+ -11) μm, the lace-shaped group cornea thickness averaged (290+ -17) μm, the haptic group cornea thickness averaged (286+ -12) μm, the suction cup group cornea thickness thinned, the average (207+ -28) μm, the full-aperture/haptic group cornea thickness averaged (294+ -21) μm, and the full-aperture/suction cup/haptic group cornea thickness averaged (306+ -15) μm. After perforation (limiting perforation area), the cornea stroma can be maintained transparent, the cornea stroma is not obviously thinned, the perforated artificial cornea endothelial sheet is better attached to the cornea stroma, and the postoperative implant falling rate is reduced.
TABLE 1 treatment and results for implantation of perforated and unperforated artificial endothelial sheets
a P < 0.05 for comparison with the unpunctured group
Although specific embodiments of the invention have been described in detail, those skilled in the art will appreciate. Numerous modifications and substitutions of details are possible in light of all the teachings disclosed, and such modifications are contemplated as falling within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.